We have developed liposomal particles that can be activated by exogenous energy sources, thus locally delivering drugs. For particles that can be activated by ultrasound, we have found that a 60 fold increase in delivery of hydrophilic molecules (as compared to free drug administration) can be achieved at 24 hours. In order to activate particles with ultrasound using mild heating, a short acyl (or single acyl) chain must be incorporated-as a result, the particles are not fully stable during circulation. In order to improve stability during circulation, we have designed particles with a longer acyl chain that can deliver a greater dose increase but require a new method for activation. By incorporating nanogold within the lipid bilayer of the particles (where the ~1 nm gold is attached to the lipid head group), these particles can be heated using electromagnetic waves, releasing the drug in any region deep within the body and achieving a 200 fold increase in drug accumulation. Although the gold particles can also be used to directly ablate a region, we feel that their use to locally deliver a drug in a safe and efficacious manner could be important in cancer therapeutics and therefore we will develop the system and particles to deliver hydrophilic molecules using electromagnetic energy. As a proof of concept, we will load the particles with a hydrophilic drug and demonstrate delivery and efficacy in a murine tumor model. The specific aims of this R21 proposal are to: quantify, refine and enhance the RF-EM heating device for heating gold nanoparticles, test and improve thermally- sensitive release of cargo from liposomes using gold nanoparticles, compare delivered dose of hydrophilic drug in implanted tumor models using RF-EM method vs. ultrasound heating and as a function of treatment duration, demonstrate efficacy of drug release in implanted tumor models. PUBLIC HEALTH RELEVANCE: Currently, one in 4 deaths in the United States is due to cancer. Available options for preemption and treatment are limited by the toxicity profiles of various drugs. As a result, substantial efforts have been directed to develop nanotechnology-based methods for increasing the efficacy and decreasing the toxicity of drug therapies. Electromagnetic waves can be used to release drugs from vehicles, even deep within the brain or thorax. Ultrasound waves can heat tissues and indirectly heat particles. Here, we have build a device for releasing hydrophilic drugs from vehicles and compare ultrasound and electromagnetic methods for drug delivery.